Pyrimidine Biosynthesis

Question 1

describe the biosynthesis of UTP

Answer 1

Question 2

describe the regulation of pyrimidine synthesis

Answer 2

• CPS-II is the regulatory step of pyrimidine biosynthesis
• CPS-II is inhibited by the end product, UTP, by feedback inhibition
• CPS II is activated by ATP and PRPP
  
  • ensures equal concentration of purine and pyrimidine nucleotides
• OPRT and OMP decarboxylase are different activities present on the same polypeptide chain
  
  • enzyme also known as UMP synthase

Question 3

describe the conversion of ribonucleotides to deoxyribonucleotides

Answer 3

Question 4

describe the formation of CTP

Answer 4

Question 5

describe the synthesis of thymidine

Answer 5

Question 6

which anticancer drugs can be used in the thymidine synthesis pathway?

Answer 6

• 5-fluorouracil is converted to 5 fluoro dUMP
  
  • this pyrimidine analog irreversibly binds to thymidylate synthase and inactivates it (suicide inhibitor)
• Methotrexate competitively inhibits dihydrofolate reductase and prevents the formation of THF
  
  • methotrexate is an inhibitor or purine and thymidine biosynthesis

Question 7

explain folate requirement and purpose

Answer 7

• Folate (folic acid) is a vitamin required in the diet of humans
• Folate as formyl-THF or methylene-THF is required for purine nucleotide synthesis and for thymidine synthesis
• Critical for rapidly dividing cells

Question 8

explain folate deficiency

Answer 8

• Folate deficiency manifests as macrocytic anemia and decreased rates of cell division
• Pre and perinatal folate deficiency in the expectant mother: higher incidence of neural tube defects in the fetus

Question 9

what is an inherited defect in pyrimidine nucleotide synthesis

Answer 9

• orotic aciduria
• deficiency of OPRT and/or OMP decarboxylase (UMP synthase)
• Poor growth, megaloblastic anemia and orotic aciduria
• Deficiency of pyrimidiens results in decreased RBC formation
• Administration of uridine improves anemia
  
  • uridine is used for synthesis of thymidine and cytidine
• UTP is a feedback inhibitor of CPS II, uridine administration results in a fall in orotic acid levels

Question 10

orotic aciduria due to urea cycle defect

Answer 10

• orotic aciduria is also found as an additional feature in hyperammonemia type II
• increased amounts of carbamoyl phosphate that is formed in the mitochondria (urea cycle), diffused into the cytosol and is used for pyrimidine biosynthesis causing increased formation of orotic acid and orotic aciduria
• How to differentiate between orotic aciduria due to urea cycle defect and pyrimidine biosynthesis defect??
  
  • look at the blood ammonia levels